Clinical studies have demonstrated the remarkable efficacy of immunomodulatory drugs (IMiDs) for the treatment of Multiple Myeloma (MM). Indeed, Thalidomide and its structural analogs Lenalidomide and Pomalidomide are drugs with billions of dollars in sales annually. However only 15-30% of relapsed patients respond to single agent drug and a majority of those patients who respond to treatment eventually develop acquired drug resistance. We have investigated the functional role of cereblon (CRBN), a primary target of Thalidomide, in the anti-MM activity of IMiDs and demonstrated that CRBN is absolutely required for the anti- cancer and immune activity of Thalidomide, Pomalidomide and Lenalidomide. We recently identified the first genomic inactivating mutations in CRBN in highly drug resistant patients and have demonstrated that gene expression levels of CRBN can predict response and survival outcomes in MM patients receiving IMiDs. We and others identified interferon regulatory factor 4 (IRF4) as one of the key downstream targets of CRBN-associated signaling, associated with IMiD drug resistance. Thus the CRBN-IRF4 axis is a target for development of new therapeutics with broad application in hematologic malignancies and immune system manipulation. These findings and the clinical, cellular and molecular toolkits already developed by our team open the door to development of clinical predictors of response and the identification of targets including not only CRBN itself, but also its downstream effectors to overcome IMiD resistance. The three aims of this study are: 1. We will construct a 635 patient tissue microarray (TMA) and use quantitative AQUA immunoflourescence (IF) or IHC to validate effectors of IMiD drug resistance. 2. In a prospective clinical trial in IMiD refractory Myeloma we will generate data on the frequency of CRBN pathway mutation contributing to drug resistance. 3. We will integrate genome wide RNA interference screening and MS proteomics to identify novel targets downstream of CRBN as potential entry points in the future development of therapeutics.